Abstract: A major outstanding challenge in biology is to understand how the exact same genomic sequence present in every cell takes on alternate epigenetic landscapes to confer a myriad of cellular functions, all while using ubiquitous cellular machinery. In addition to histone modifications and DNA methylation, RNA has been long thought to be involved in the establishment and inheritance of these epigenetic states, but is far less understood. Indeed, recently three examples of large non-coding RNAs (HOTAIR, XIST and AIR) have been discovered that share a common theme: they physically associate with chromatin remodeling complexes and are required to guide chromatin formation at specific genomic loci. Although these examples suggest a general mechanism it is still unclear to what extent RNA plays a role in chromatin formation and the mechanisms by which this guidance occurs. Here we propose to comprehensively and systematically address the roles of large non-coding RNAs in the formation of chromatin structure. We will accomplish this by : (1) Identifying and characterize large noncoding RNAs that physically associate with chromatin remodeling complexes genome-wide across multiple yet related cell contexts;(2) Define the sites of regulations and the guidance mechanism to these genomic loci (3) Identify how these molecules and their mechanisms are misregulated in human disease. Together, our multifaceted experimental and computational approaches aim to 'crack the code'of epigenetic establishment and maintenance. This will transform our understanding of genome regulation and establish a new paradigm for RNA in the guidance of chromatin formation. Public Health Relevance: Our research aims to understand a universal problem in human health: How does the same genome present in every cell take on alternate identities that orchestrate distinctive cell states and how are these states misregulated in diseases such as cancer. We recently discovered a novel class of large intergenic non-coding RNAs (lincRNAs) that have the ability to regulate cellular identity and are misregulated in human cancers. Thus, we seek to establish the fundamental principles and mechanisms by which lincRNAs regulate cellular identity and their role in human cancers. The ultimate goal of these innovative experimental and computational approaches is to develop novel RNA based cancer therapeutics.